Tissue and fluid penetration of garenoxacin in surgical patients.

BACKGROUND AND PURPOSE: Garenoxacin is a novel des-F(6)-quinolone that exhibits broad-spectrum activity against a wide range of aerobic and anaerobic pathogens of clinical importance. This study examined the penetration of garenoxacin into sinus mucosa, incisional skin, subcutaneous tissue, bile, adipose tissue, striated muscle, bone, gallbladder wall, liver, small and large bowel mucosa, and mesenteric lymph nodes relative to the plasma concentration after an oral 600 mg dose. METHODS: A series of 30 patients, ages 20 to 83 years, undergoing elective surgery were enrolled. Patients received a single 600 mg oral dose of garenoxacin before surgery. Blood and tissue specimens were collected at surgery 3-5 h post-dose, and garenoxacin concentrations were determined using validated liquid chromatography/tandem mass spectrometry assays designed specifically for each tissue and biofluid. RESULTS: The mean plasma or bile (mcg/mL) and tissue (mcg/g) concentrations ( +/- standard deviation) were plasma 5.71 +/- 3.44, bile 7.59 +/- 9.96, adipose tissue 0.90 +/- 0.54, subcutaneous tissue 1.19 +/- 1.23, incisional skin 3.06 +/- 1.74, striated muscle 3.92 +/- 2.54, bone 2.82 +/- 2.42, sinus mucosa 5.26 +/- 3.84, liver 1.84 +/- 0.75, gallbladder 11.59 +/- 11.94, large intestine 12.13 +/- 9.34, small intestine 15.66 +/- 19.20, and mesenteric lymph node 3.10 +/- 2.44. CONCLUSION: After a single 600 mg oral dose, garenoxacin penetrates well into selected tissues and fluids. In addition, the tissue and fluid concentrations at 3-5 hours post-dose exceeded the minimum inhibitory concentration-90% of most targeted pathogens, suggesting that garenoxacin would be effective in the treatment of sinus, skin and skin structure, and intra-abdominal infections.

Population pharmacokinetics and pharmacodynamics of garenoxacin in patients with community-acquired respiratory tract infections.

Garenoxacin (T-3811ME, BMS-284756) is a novel, broad-spectrum des-F(6) quinolone currently under study for the treatment of community-acquired respiratory tract infections. This analysis assessed garenoxacin population pharmacokinetics and exposure-response relationships for safety (adverse effects [AE]) and antimicrobial activity (clinical cure and bacteriologic eradication of Streptococcus pneumoniae and the grouping of Haemophilus influenzae, Haemophilus parainfluenzae, and Moraxella catarrhalis). Data were obtained from three phase II clinical trials of garenoxacin administered orally as 400 mg once daily for 5 to 10 days for the treatment of community-acquired pneumonia, acute exacerbation of chronic bronchitis, and sinusitis. Samples were taken from each patient before drug administration, 2 h following administration of the first dose, and on the day 3 to 5 visit. Individual Bayesian estimates of the fu (fraction unbound), the Cmax, and the fu for the area under the concentration-time curve from 0 to 24 h (fu AUC(0-24)) were calculated as measurements of drug exposure by using an ex vivo assessment of average protein binding. Regression analysis was performed to examine the following relationships: treatment-emergent AE incidence and AUC(0-24), Cmax, or patient factors; clinical response or bacterial eradication and drug exposure (fu Cmax/MIC, fu AUC(0-24)/MIC, and other exposure covariates); or disease and patient factors. Garenoxacin pharmacokinetics were described by a one-compartment model with first-order absorption and elimination. Clearance was dependent on creatinine clearance, ideal body weight, age, obesity, and concomitant use of pseudoephedrine. The volume of distribution was dependent on weight and gender. Patients with mild or moderate renal dysfunction had, on average, approximately a 16 or 26% decrease in clearance, respectively, compared to patients of the same gender and obesity classification with normal renal function. AE occurrence was not related to garenoxacin exposure. Overall, clinical cure and bacterial eradication rates were 91 and 90%, respectively, for S. pneumoniae and 93 and 92%, respectively, for the grouping of H. influenzae, H. parainfluenzae, and M. catarrhalis. The fu AUC(0-24)/MIC ratios were high (>90% were >200), and none of the pharmacokinetic-pharmacodynamic exposure measurements indexed to the MIC or other factors were significant predictors of clinical or bacteriologic response. Garenoxacin clearance was primarily related to creatinine clearance and ideal body weight. Although garenoxacin exposure was approximately 25% higher for patients with moderate renal dysfunction, this increase does not appear to be clinically significant as exposures in this patient population were not significant predictors of AE occurrence. Garenoxacin exposures were at the upper end of the exposure-response curves for measurements of antimicrobial activity, suggesting that 400 mg of garenoxacin once daily is a safe and adequate dose for the treatment of the specified community-acquired respiratory tract infections.

Characterization of the penetration of garenoxacin into the breast milk of lactating women.

The primary objective of this study was to characterize the extent of excretion of garenoxacin, a novel des-F(6)-quinolone antimicrobial, into the breast milk of lactating women. A secondary objective was to determine the time after dose administration that garenoxacin was no longer detected in breast milk so as to define when a mother may resume breastfeeding if it was interrupted for garenoxacin administration. Six healthy, lactating women (age [mean +/- SD]: 32 +/- 6 years; weight: 68.3 +/- 19.8 kg; body mass index: 26 +/- 5 kg/m(2)) who had completed weaning their infants were administered a single 600-mg oral dose of garenoxacin. Plasma samples were collected predose and repeatedly up to 72 hours postdose. Breast milk was collected predose and for 6- to 12-hour intervals repeatedly up to 120 hours postdose. Breast milk/plasma concentration ratios for garenoxacin ranged from 0.35 to 0.44 up to 24 hours postdose, and the mean peak breast milk concentration was 3.0 microg/mL (0- to 6-h collection interval). Overall, garenoxacin exposure in breast milk was minimal, with a mean of 0.07% of the administered dose recovered within 120 hours. Indeed, garenoxacin was undetectable in the breast milk of a majority of subjects within 84 hours of dosing. As such, an infant nursing from a mother who had received a single 600-mg oral dose of garenoxacin could theoretically be exposed to 0.42 mg of garenoxacin (0.105 mg/kg/day for a 4-kg infant over the period of 5 days of nursing). If extrapolated to a 14-day course of garenoxacin 600 mg once daily, total exposure would be approximately 5.88 mg. These findings indicate that, like other quinolone antimicrobials, garenoxacin is secreted in breast milk.

Effect of a high-fat meal on the pharmacokinetics of the des-F(6)-quinolone BMS-284756.

STUDY OBJECTIVE: To evaluate the effects of a high-fat meal on the systemic exposure of oral BMS-284756. DESIGN: Open-label, randomized, two-way crossover study. SETTING: Clinical research facility. SUBJECTS: Fourteen healthy individuals. INTERVENTIONS: Participants received two single 400-mg doses of BMS-284756, separated by at least 1 week. One dose was given while participants were fasting, and one dose was given within 5 minutes of consumption of a high-fat meal. MEASUREMENTS AND MAIN RESULTS: Serial blood samples were collected, and plasma samples were analyzed for BMS-284756 using a validated liquid chromatography with tandem mass spectrometry detection method. Maximum plasma concentration and area under the plasma concentration-time curve (AUC) after the high-fat meal were 19% and 11% lower, respectively, than those in the fasted state. The 90% confidence intervals for the ratios of means (0.71-0.94 and 0.85-0.93, respectively) satisfied predefined equivalence criteria. Equivalence of the AUC values for BMS-284756 in fed and fasted individuals indicates that the presence of food should not affect the efficacy of this drug. CONCLUSION: Single doses of BMS-284756 were safe and well tolerated and may be taken without regard to meals.